Modeling host–pathway dynamics at the genome scale with machine learning

Pathway engineering offers a promising avenue for sustainable chemical production. The design of efficient production systems requires understanding complex host-pathway interactions that shape the metabolic phenotype. While genome-scale metabolic models are widespread tools for studying static host-pathway interactions, it remains a challenge to predict dynamic effects such as metabolite accumulation or enzyme overexpression during the course of fermentation. Here, we propose a novel strategy to integrate kinetic pathway models with genome-scale metabolic models of the production host. Our method enables the simulation of the local nonlinear dynamics of pathway enzymes and metabolites, informed by the global metabolic state of the host as predicted by Flux Balance Analysis (FBA). To reduce computational costs, we make extensive use of surrogate machine learning models to replace FBA calculations, achieving simulation speed-ups of at least two orders of magnitude. Through case studies on two production pathways in Escherichia coli, we demonstrate the consistency of our simulations and the ability to predict metabolite dynamics under genetic perturbations and various carbon sources. We showcase the utility of our method for screening dynamic control circuits through large-scale parameter sampling and mixed-integer optimization. Our work links together genome-scale and kinetic models into a comprehensive framework for computational strain design.